Bepridil differentially inhibits two delayed rectifier K+ currents, IKr and IKs, in guinea‐pig ventricular myocytes

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Abstract
We investigated the effects of bepridil on the two components of the delayed rectifier K+ current, i.e., the rapidly activating (IKr) and the slowly activating (IKs) currents using tight‐seal whole‐cell patch‐clamp techniques in guinea‐pig ventricular myocytes, under blockade of L‐type Ca2+ current with nitrendipine (5 μM) or D600 (1 μM). Bepridil decreased IKs under blockade of IKr with E4031 (5 μM), in a concentration‐dependent manner. The concentration‐dependent inhibition of IKs by bepridil was fitted by a curve, assuming one‐to‐one interactions between the channel and the drug molecule. The concentration of half‐maximal inhibition (IC50) was found to be 6.2 μM. The effect of bepridil on IKr was assessed using an envelope‐of‐tails test. In the control condition, a ratio of the tail current to the time‐dependent current measured during depolarization was large (>1) at shorter pulses (Kr, the drug was found to block IKr in a cooperative manner (Hill coefficient=3.03) and the IC50 was 13.2 μM. These results suggest that bepridil at a clinical therapeutic concentration (∼2 μM) selectively blocks IKs but does not inhibit IKr. This may relate to the characteristic frequency‐dependent effects of bepridil on the action potential duration (APD), e.g., the non‐reverse use‐dependent prolongation of APD. British Journal of Pharmacology (1999) 128, 1733–1738; doi:10.1038/sj.bjp.0702959